Frazier James L, Wang Paul P, Case Daniel, Tyler Betty M, Pradilla Gustavo, Weingart Jon D, Brem Henry
Department of Neurological Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
J Neurooncol. 2003 Sep;64(3):203-9. doi: 10.1023/a:1025695423097.
Minocycline, a tetracycline derivative, has been shown to inhibit tumor angiogenesis through inhibitory effects on matrix metalloproteinases. Previous studies have shown this agent to be effective against a rodent brain tumor model when delivered intracranially and to potentiate the efficacy of standard chemotherapeutic agents. In the present study, the in vivo efficacy of intracranial minocycline delivered by a biodegradable controlled-release polymer against rat intracranial 9L gliosarcoma was investigated to determine whether it potentiates the effects of systemic 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU). Minocycline was incorporated into the biodegradable polymer polyanhydride poly[bis(p-carboxyphenoxy)propane-sebacic acid] (pCPP:SA) at a ratio of 50:50 by weight. The release kinetics of minocycline from the polymer were assessed. For the efficacy studies, female Fischer 344 rats were implanted with 9L glioma. Treatment with minocycline delivered by the pCPP:SA polymer at the time of tumor implantation resulted in 100% survival in contrast to untreated control animals that died within 21 days. Treatment with the minocycline-polymer 5 days after tumor implantation provided only modest increases in survival. The combination of intracranial minocycline and systemic BCNU extended median survival by 82% compared to BCNU alone (p < 0.0001) and 200% compared to no treatment (p < 0.004). We conclude that local intracranial delivery of minocycline from biodegradable controlled-release polymers inhibits tumor growth and may have clinical utility when combined with a chemotherapeutic agent.
米诺环素是一种四环素衍生物，已被证明可通过抑制基质金属蛋白酶来抑制肿瘤血管生成。先前的研究表明，该药物经颅内给药时对啮齿动物脑肿瘤模型有效，并能增强标准化疗药物的疗效。在本研究中，研究了通过可生物降解的控释聚合物递送的颅内米诺环素对大鼠颅内9L胶质肉瘤的体内疗效，以确定它是否能增强全身应用1,3-双（2-氯乙基）-1-亚硝基脲（BCNU）的效果。米诺环素以重量比50:50掺入可生物降解的聚合物聚酸酐聚[双（对羧基苯氧基）丙烷-癸二酸]（pCPP:SA）中。评估了米诺环素从聚合物中的释放动力学。在疗效研究中，给雌性Fischer 344大鼠植入9L胶质瘤。在肿瘤植入时用pCPP:SA聚合物递送的米诺环素进行治疗，结果100%存活，而未治疗的对照动物在21天内死亡。在肿瘤植入后5天用米诺环素-聚合物治疗仅使存活率有适度提高。与单独使用BCNU相比，颅内米诺环素与全身BCNU联合使用使中位生存期延长了82%（p<0.0001），与未治疗相比延长了200%（p<0.004）。我们得出结论, 从可生物降解的控释聚合物进行颅内局部递送米诺环素可抑制肿瘤生长，与化疗药物联合使用时可能具有临床应用价值。
